This invention relates to a process for the preparation of cephalosporin compounds and intermediates for the synthesis of such compounds.
WO 92/01696 discloses compounds of formula (I): 
wherein R1 is hydrogen, methoxy or formamido; R2 is an acyl group, in particular that of an antibacterially active cephalosporin; CO2R3 is a carboxy group or a carboxylate anion, or R3 is a readily removable carboxy protecting group (such as a pharmaceutically acceptable in vivo hydrolysable ester group); R4 represents hydrogen or up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, CO2R, CONR2, SO2NR2 (where R is hydrogen or C1-6 alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R4 alkyl substituent is optionally substituted by any other R4 substituent; X is S, SO, SO2, O or CH2; and m is 1 or 2; and salts thereof. Compounds of formula (I) have antibacterial activity.
WO 92/01696 discloses various methods of synthesis of compounds of formula (I). It is an object of the present invention to provide alternative process enabling more convenient methods of synthesis of compounds of formula (I). Other objects and advantages of the present invention will be apparent from the following description.
According to the present invention a process for the preparation of a compound of formula (II) is provided 
which process includes the step of cyclising a compound of formula (II): 
wherein in formulae (II) and (III) R1, R2, R3, R4, X and m are as defined in formula (I) above and the dotted line indicates that the compounds (II) and (III) may be a 2-cephem or a 3-cephem system, and where in formula (III) the substituent(s) R4 when other than hydrogen may replace any of the hydrogen atoms bonded to carbon atoms in the side chain.
In compounds (II) the bonding carbon atom of the cyclic ether moiety which links the ring to the cephalosporin nucleus is asymmetric. The present invention includes either stereoisomer, as well as mixtures of both isomers.
In compounds of formula (II) wherein R1 is formamido, the formamido group can exist in conformations wherein the hydrogen atoms of the xe2x80x94NHxe2x80x94CHO moiety are cis- or trans-; of these the cis conformation normally predominates.
Preferred compounds within formula (II) are pharmaceutically acceptable, iande are compounds of formula (IIA) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof: 
wherein R1, R2, R4, m and X are as defined with respect to formula (II) and the group CO2R5 is CO2R3 where CO2R3 is a carboxy group or a carboxylate anion.
Those compounds of the formula (II) wherein R3 is a readily removable carboxy protecting group other than a pharmaceutically acceptable in vivo hydrolysable ester or which are in non-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (IIa) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.
Suitable readily removable carboxy protecting groups for the group R3 include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved in vivo.
It will be appreciated that also included within the scope of the invention are processes for the preparation of salts and carboxy-protected derivatives, including in vivo hydrolysable esters, of any carboxy groups that may be present as optional substituents in compounds of formula (II) or (IIa). Also included within the scope of the invention are processes for the preparation of acid addition salts of any amino group or substituted amino group that may be present as optional substituents in compounds of formula (II) or (IIa).
Suitable ester-forming carboxyl-protecting groups R3 are those which may be removed under conventional conditions. Such groups include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, t-butyl, t-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, p-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus-containing group, an oxime radical of formula xe2x80x94Nxe2x95x90CHR7 where R7 is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below.
When used herein the term xe2x80x98arylxe2x80x99 includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C1-6) alkyl, phenyl, (C1-6) alkoxy, hydroxy(C1-6)alkyl, mercapto(C1-6)alkyl, halo(C1-6)alkyl, hydroxy, amino, nitro, carboxy, (C1-6) alkylcarbonyloxy, alkoxycarbonyl, formyl, or (C1-6)alkylcarbonyl groups.
The terms xe2x80x98heterocyclylxe2x80x99 and xe2x80x98heterocyclicxe2x80x99 as used herein include aromatic and non-aromatic, single and fused, rings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstituted or substituted by, for example, up to three groups selected from halogen, (C1-6)alkyl, (C1-6)alkoxy, halo(C1-6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C1-6)alkoxycarbonyl, (C1-6)alkoxycarbonyl(C1-6)alkyl, aryl, and oxo groups. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. The term xe2x80x98heteroarylxe2x80x99 refers to heteroaromatic heterocyclic rings. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention.
The term xe2x80x98heteroarylxe2x80x99 as used herein means a heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring atoms in each ring.
When used herein the terms xe2x80x98alkylxe2x80x99 alkenyl, alkynyl and xe2x80x98alkoxyxe2x80x99 include straight and branched chain groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl. A particular alkyl group is methyl.
When used herein the term xe2x80x98halogenxe2x80x99 refers to fluorine, chlorine, bromine and iodine.
A carboxyl group may be regenerated from any of the above esters by usual methods appropriate to the particular R3 group, for example, acid- and base-catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected.
Examples of suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v): 
wherein Ra is hydrogen, (C1-6) alkyl, (C3-7) cycloalkyl, methyl, or phenyl, Rb is (C1-6)alkyl, (C1-6)alkoxy, phenyl, benzyl, (C3-7) cycloalkyl, (C3-7) cycloalkyloxy, (C1-6) alkyl (C3-7)cycloalkyl, 1-amino (C1-6)alkyl, or 1-(C1-6)alkyl) amino (C1-6) alkyl; or Ra and Rb together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; Rc represents (C1-6)alkylene optionally substituted with a methyl or ethyl group and Rd and Re independently represent (C1-6)alkyl; Rf represents (C1-6)alkyl; Rg represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (C1-6)alkyl, or (C1-6)alkoxy; Q is oxygen or NH; Rh is hydrogen or (C1-6)alkyl; Ri is hydrogen, (C1-6)alkyl optionally substituted by halogen, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, aryl or heteroaryl; or Rh and Ri together form (C1-6)alkylene; Rj represents hydrogen, (C1-6)alkyl or (C1-6)alkoxycarbonyl; and Rk represents (C1-8)alkyl, (C1-8)alkoxy, (C1-6)alkoxy(C1-6)alkoxy or aryl.
Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, xcex1-acetoxyethyl, xcex1-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, (xcex1-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second xcex2-lactam antibiotic or to a xcex2-lactamase inhibitor.
A further suitable pharmaceutically acceptable in vivo hydrolysable ester group is that of the formula: 
wherein R5 is hydrogen, C1-6 alkyl or phenyl.
Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (II) include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, especially sodium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)-amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, N,N-dibenzylethylene-diamine, 1-ephenamine, N-methylmorpholine, N-ethylpiperidine, N-benzyl-xcex2-phenethylamine, dehydroabietylamine, N,Nxe2x80x2-bisdehydro-abietylamine, ethylenediamine, or bases of the pyridine type such as pyridine, collidine or quinoline, or other amines which have been used to form salts with known penicillins and cephalosporins. Other useful salts include the lithium salt and silver salt. Salts within compounds of formula (I), may be prepared by salt exchange in conventional manner.
In compounds of formula (II), (IIa), and (III) the group X may be sulphur or an oxidised sulphur atom, i.e. a sulphoxide (SO) or sulphone (SO2) group. When X is a sulphoxide group it will be understood that xcex1- and xcex2-isomers may exist; processes for the preparation of both such isomers are encompassed within the scope of the present invention.
Examples of X include S, SO, SO2, O and CH2.
Preferably X is S, O or CH2.
Advantageously R1 is hydrogen.
Suitably, the cyclic ether at the 3-position of the cephalosporin nucleus in formulae (II) and (IIA) is unsubstituted or substituted by up to three substituents, R4, selected from (C1-6)alkyl, for example methyl, (C1-6)alkoxy, for example methoxy, (C1-6)alkoxycarbonyl for example methoxycarbonyl, (C1-6)alkoxy (C1-6)alkyl, for example methoxymethyl, and (C1-6)alkanoyloxy (C1-6)alkyl, for example acetoxymethyl. Preferably the cyclic ether at the 3-position of the cephalosporin nucleus is unsubstituted.
Preferably m is 1, so that the cyclic ether at the 3-position in formulae (II) and (IIA) is a tetrahydrofuranyl system, in particular an (S)-tetrahydrofuran-2-yl ring system, i.e.: 
Suitable acyl groups R2 include those of formulae (a)-(f): 
wherein p is 0, 1 or 2; m is 0, 1 or 2; A1 is (C1-6) alkyl, substituted (C1-6) alkyl, (C3-6) cycloalkyl, cyclohexenyl, cyclohexadienyl, an aromatic (including heteroaromatic) group, such as phenyl, substituted phenyl, thienyl, pyridyl, or an optionally substituted thiazolyl group, a (C1-6) akylthio group or (C1-6) alkyloxy; X1 is a hydrogen or halogen atom, a carboxylic acid, carboxylic ester, sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, acylamino, heterocyclylamino, guanidino or acylureido group; A2 is an aromatic group, for example a phenyl, 2,6-dimethoxyphenyl,2-alkoxy-1-naphthyl, 3-arylisoxazolyl, or a 3-aryl-5-methylisoxazolyl group, such as 3-(2chloro-6-fluorophenyl)-5-methylisoxazol-4-yl;
a substituted alkyl group; or a substituted dithietane; X2 is a xe2x80x94CH2OCH2xe2x80x94, xe2x80x94CH2SCH2xe2x80x94 or alkylene group; X3 is an oxygen or sulphur atom; A3 is an aryl or heteroaryl group such as phenyl, substituted phenyl, furyl, aminothiazolyl or aminothiadiazolyl in which the amino group is optionally protected; and A4 is hydrogen, (C1-6)alkyl, (C3-8) cycloalkyl, (C3-8) cycloalkyl(C1-6)alkyl, (C1-6) alkoxycarbonyl(C1-6) alkyl, (C2-6) alkenyl, carboxy(C1-6)alkyl, (C2-6) alkynyl, aryl or (C1-6)alkyl substituted by up to three aryl groups.
Suitably when R2 is a group (a), A1 is (C1-6) alkyl, (C3-6) cycloalkyl, cyclohexenyl, cyclohexadienyl, phenyl, substituted phenyl such as hydroxyphenyl, thienyl or pyridyl; and X1 is a hydrogen or halogen atom, or a carboxy, carboxylic ester, azido, tetrazolyl, hydroxy, acyloxy, optionally protected amino, ureido, guanidino or acylureido group.
Suitably when R2 is a group of formula (d), A2 is phenyl, X3 is oxygen and p is O.
Alternatively when R2 is a group of formula (e) or (f) suitable values for the group A3 include those commonly found in antibacterially active cephalosporins containing a hydroxyimino, substituted hydroxyimino or vinyl group in the side chain attached to position 7 of the cephalosporin nucleus, for example phenyl, thien-2-yl, thien-3-yl, fur-2-yl, fur-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-amino-1,2,4-thiadiazol-3-yl and 2-aminothiazol-4-yl in each of which the amino group is optionally protected.
Preferred groups for A3 include phenyl, 2-aminothiazol-4-yl, fur-2-yl, thien-2-yl, 2-(2-chloroacetamido)thiazol-4-yl, 2-tritylamino-thiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl and 4-aminopyrimid-2-yl.
In compounds of formula (Ia), a particularly preferred group for A3 is 2-aminothiazol-4-yl.
Suitable values for the group A4 include hydrogen, methyl, ethyl, cyclopropylmethyl, triphenylmethyl (trityl), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, carboxymethyl, carboxypropyl and t-butoxycarbonylmethyl.
Preferred values for A4 in compounds of formula (IIa) or (III) include methyl and hydrogen.
It will be appreciated that compounds of the invention wherein R2 is a group of formula (e) (or (f)) can exist as syn and anti (or E and Z) isomers or mixtures thereof. Both isomers are encompassed within the scope of this invention.
Preferably the compounds of formula (IIa) or (III) wherein R2 is a group of formula (e) have the syn configuration (i.e. have the group OA4 syn to the amide linkage) or are enriched in that isomer.
Similarly, when R2 is a group of formula (f), the group A4 is preferably cis to the amide linkage, i.e. when group (f) is 2-amino-thiazol-4-yl, the Z-configuration is preferred.
Certain compounds of formula (II), (IIA) or (III) include an amino group which may be protected. Suitable amino protecting groups are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule.
Examples of amino protecting groups include (C1-6) alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (C1-4) alkyl, (C1-4) alkoxy, trifluoromethyl, halogen, or nitro; (C1-4) alkoxycarbonyl; benzyloxycarbonyl or trityl substituted as for benzyl above; allyloxycarbonyl, trichloroethoxycarbonyl or chloroacetyl.
Some of the compounds of formula (III) may be crystallised or recrystallised from solvents such as organic solvents. In such cases solvates may be formed. This invention includes within its scope processes in which stoichiometric solvates of compounds of formula (II) including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation, are prepared.
Suitable and preferred configurations and substituents of the compound of formula (III) are as discussed above by analogy with compounds of formula (II). It will be appreciated that the compounds (III) may exist in a number of diastereoisomers, and all of these are encompassed within formula (III). For example when m is 1 the 1,4-dihydroxylbut-1-yl side chain can exist in two diastereoisomers, one of which is more polar than the other. The less polar of these is preferred as it appears to lead to preferential formation of the (S)-tetrahydro furan-2-yl ring system. These isomers may be separated by conventional procedures such as chromatography.
The cyclisation reaction of the process of the invention may suitably be carried out by treatment of the compounds (III) with an acid catalyst, for example an inorganic acid such as hydrochloric acid or an organic acid, such as an organic sulphonic acid such as an arylsulphonic acid, eg toluene-4-sulphonic acid. Alternatively the cyclisation reaction may be carried out by treatment of the compounds (III) With an acylating agent, such as an acid anhydride, for example trifluoromethane sulphonic anhydride, in the presence of a base such as triethylamine or lutidine. Compounds (II) exist as two diastereoisomers, and these may be cyclised stereospecifically by the use of an acylating agent as described above. The reaction may be suitably carried out in an organic solvent, such as a halogenated hydrocarbon, eg dichloromethane, which is preferably pre-dried. Suitably the reaction is carried out at reduced temperature, eg below 0xc2x0 C., such as below xe2x88x9220xc2x0 C., eg at around xe2x88x9270xc2x0 C. After reaction the mixture may be worked up and the product compound isolated by conventional methods.
Compounds of formula (III) may be prepared from known compounds of formula (IV): 
where R1, R2, R3 and X are as defined above. Suitably R2 may be an amino-protecting group such as those discussed above, for example phenylacetyl (so that R2NH is a phenylacetamido group), and R3 may be an ester forming carboxyl-protecting group such as those discussed above, for example diphenylmethyl or p-methoxybenzoyl. Compounds (IV) are disclosed in H. Tanaka et al, Synlett. (1990) p660.
Compounds (IV) may be converted to compounds (III) in a number of ways. In one way the compound (IV) may be treated with a Grignard reagent of formula (V): 
where R4 and m are as defined with respect to formula (III) above, and X and X1 are the same or different halogen, for example X being, chlorine and X1 being bromine.
The reaction between the compound (IV) and Grignard reagent (V) may be carried out in an organic solvent such as an ether, eg THF, preferably at reduced temperature, eg less than 0xc2x0 C., eg less than xe2x88x9250xc2x0 C., eg around xe2x88x9270xc2x0 C., suitably in the presence of lithium chloride, preferably in dry conditions under an inert atmosphere such as argon. After this the reaction mixture may be worked up and the product compound (III) isolated in a conventional manner.
Grignard reagents (V) may themselves be prepared from compounds of formula (VI): 
where R4 and m are as defined in (v) above, and X and X1 are the same or different halogens, eg X may be chlorine and X1 bromine, by reaction of compounds (VI) with magnesium. This reaction may suitably be carried out in an organic solvent such as THF, in dry conditions, under an inert atmosphere, eg argon.
Compounds (VI) may themselves be prepared by reaction of compounds (VII): 
where R4 and m are as defined above X is a halogen such as chlorine, with a Grignard reagent RMgX1 where X1 is a halogen such as bromine, and R is an alkyl group such as methyl. This reaction may suitably be carried out in an organic solvent such as THF in dry conditions, under an inert atmosphere, such as argon.
The reaction from compounds (VII) to (V) may be carried out in situ.
In a second way the compound (IV) may first be converted to a compound (VIII): 
where R1, R2, R3, R4 m and X are as defined with respect to formula (III). Of the two possible configuration of the hydroxyl croup in compounds (VIII) i.e. (VIII A) and (VIII B): 
(VIII A) is preferred as leading to a preferred configuration of the 3-position cyclic ether ring in formula (II) above. The compound (VIII) may then be hydroxylated to form corresponding compounds (III) having the terminal hydroxyl group. Suitably this may be achieved by treatment of compounds (III) with borane-tetrahydrofuran complex, followed by treatment with water or dilute aqueous alkali metal hydroxide solution, and hydrogen peroxide.
Compounds of formula (IV) may be formed into compounds (VIII) by reaction with an organometallic reagent
In one such method the compound (IV) may be reacted with the Grignard reagent (IX): 
where m and R4 are as defined in formula (VIII). Z may be YMg where Y is a halogen such as chlorine or bromine, and the reaction may be carried out in an organic solvent such as THF, suitably at a reduced temperature, eg around xe2x88x9270xc2x0 C., suitably in the presence of lithium chloride.
Alternatively compounds (VIII) may be prepared stereospecifically from compounds (IV) by the use of compounds (IX) in which Z is a chirally inducing group which leads to preferential formation of a desired configuration of the hydroxyl group in the compound (VII). A suitable chirally inducing group Z is the boronate group (X): 
where Ra, Rb, Rc and Rd are independently selected from hydrogen, alkyl and protected carboxy, eg CO2Re where Re is alkyl, for example methyl. For example when Ra, Rb, Rc and Rd are all alkyl, group (X) may suitably be a pinacol boronate group. Preferably group (X) is a tartrate boronate group wherein Ra is alkylcarboxylate, Rb is hydrogen, Rc is alkylcarboxylate and Rd is hydrogen. Such boronates may be prepared by a known (JACS (1985), 107, 8186-8190) reaction in which known Grignard reagents of formula (IX) in which Z is halogen are reacted with (CH3O)3B and a dialkyl tartrate ester.
The reaction between compounds (IV) and boronates (IX) may suitably be carried out in an organic solvent such as toluene at a temperature between xe2x88x9270xc2x0 C. to +110xc2x0 C. depending on the nature of the groups Ra, Rb, Rc and Rd.
Compounds (VIII) prepared by this stereospecific route may then be hydroxylated as described above, the stereochemistry of the hydroxyl group shown in (VIII) being preserved in the resultant compounds (III) so formed, and the stereospecific compound (III) may then be stereospecifically cyclised by the use of an acylating agent as described above.
The overall stereospecific route from compounds (IV) to compounds (II) is summarised below: 
In one embodiment of the process of the invention the compound (IV) is converted into a 2-cephem compound of formula (III), i.e. of formula (III A): 
which is converted during the cyclisation process of the invention into a 2-cephem compound of formula (II), i.e. of formula (II B): 
where R1, R2, R3, R4, X and m are as defied in formulae (II) and (III) above. R2 and R3 may be the above-described amino- and carboxy-protecting groups.
The 2-cephem compound (II B) produced by this embodiment may be converted to a 3-cephem compound of formula (II). When X is sulphur conversion of 2-cephems to 3-cephems may be carried out by the generally known method of oxidising the sulphur to form the corresponding 1-oxide, followed by reduction. Oxidation may be performed by using a peroxy acid, for example m-chloroperbenzoic acid. The following reduction process may be carried out using a phosphorus (III) compound, such as phosphorus trichloride in a suitable solvent such as dimethyl formamide or dichloromethane.
When R2 and R3 are respectively amino- and carboxy-protecting groups, these may be removed and replaced by respectively an acyl group of an antibacterially active cephalosporin, and a salt forming cation or pharmaceutically acceptable in-vivo hydrolysable ester group.
An amino-protecting group R2 may be removed from the compound of formula (II) by the known Delft procedure, eg using phosphorus pentachloride in the presence of N-methylmorpholine. The resulting 6-amino compound of formula (II) having R2 as hydrogen may then be converted in an acylation reaction to a compound of formula (II) in which R2 is the acyl group of an antibacterially active cephalosporin by reaction of this amino compound with an N-acylating derivative of an acid of formula R2OH. Suitable reagents and conditions for this acylating reaction are described in WO 92/01696.
A carboxy-protecting group R3 may be removed from the compound of formula (II) by methods which are well known in cephalosporin chemistry. For example a diphenylmethyl or 4-methoxybenzyl protecting group R3 may be removed by reaction with aluminium chloride and anisole in a suitable solvent such as dichloromethane.
Salts and esters of the free acid so formed may be prepared by methods well known in cephalosporin chemistry. For example salts of formula (II) may be formed by reaction with a basic compound of a salt-forming cation, for example aqueous trisodium citrate to form sodium salts. Such a reaction may for example be carried out in aqueous conditions. Esters of formula (II), such as pharmaceutically acceptable in-vivo hydrolysable esters may also be made by methods well known in cephalosporin chemistry. For example esters may be formed by reaction of an alkali metal salt of formula (II) with a compound of formula R3X where X is a halogen such as iodine and R3 is the ester-forming group, for example acetoxymethyl or pivaloyloxy methyl. Such a reaction may be carried out in an organic solvent such as toluene or N-methylpyrrolidone.
During the course of the reactions described above, mixtures of isomers may be formed. The process of the invention includes the preparation of such isomeric mixtures Isomers produced in the course of these reactions may be separated by conventional techniques such as chromatography.
Certain of the compounds described herein and formed as intermediates in the preparation of compounds of formula (II) are believed to be novel and form a further aspect of this invention, for example compounds of formula (II B), (III), (III A) and (VIII).
Pharmaceutical uses for the compounds of formula (II) are described in WO 92/01696.